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A team led by Richard Gilbertson, MD, PhD, Developmental Neurobiology, is studying genes whose expression accurately reports the presence of gene mutations in biochemical pathways in medulloblastoma. These genes can be compared to “light bulbs” that are triggered when a specific biochemical pathway is abnormally activated in a tumor. Using these genes as signatures of the pathways, researchers hope to speed future development of more effective and less toxic treatments for medulloblastoma.

“Our strategy lets us quickly determine which signaling pathway is abnormally activated by identifying in tumor samples the tell-tale genes that indicate which genes are mutated,” said Gilbertson.

The technique could also be used to identify specific pathways in other types of cancer that might be vulnerable to novel therapies, and therefore speed development of so-called molecular-targeted therapies for a wide variety of cancers, he added. Molecular-targeted therapies work by blocking individual molecules that are key triggers of disease.

This new approach would avoid trial-and-error therapy that fails in patients who are not ideal candidates for a specific treatment, Gilbertson explained. It would also reduce the chance that otherwise effective drugs would be abandoned because they failed in such patients during clinical trials. Gilbertson, co-director of the St. Jude Neurobiology and Brain Tumor Program, is senior author of a paper on this work that appears in the April 20 issue of Journal of Clinical Oncology, which now appears in the online edition of that publication.

The key to the strategy is the ability to determine in individual children which biochemical signaling pathway triggers and sustains the cancer by identifying key genes that are linked to a particular pathway. The investigators proved that this strategy is valid by demonstrating it is possible to assign children with medulloblastoma to specific groups, depending on which biochemical signaling pathway is abnormally active. Based on this classification, novel drugs designed to block a key protein in each specific pathway could be correctly administered to the children most likely to respond to them.

Margaret Thompson, MD, PhD, formerly a clinical fellow in the Gilbertson lab, is the paper’s first author. Other St. Jude authors of the study include Tom Curran, PhD, and Twala Hogg, Developmental Neurobiology; James Dalton, Pathology; David Finkelstein, PhD, Hartwell Center; Amar Gajjar, MD, Hematology-Oncology; and Christine Fuller, MD, formerly of Pathology.